Detection of cholangiocarcinoma in primary sclerosing cholangitis by positron emission tomography

Primary sclerosing cholangitis (PSC) predisposes to cholangiocarcinoma (CC), which usually is widespread in the liver at the time of the diagnosis and which has a median survival of approximately 6 months. Positron emission tomography (PET) is a noninvasive scanning method that allows the assessment of metabolism in vivo by means of positron-emitting radiolabeled tracers. [18F]Fluoro-2-deoxy-D-glucose (FDG) is a glucose analogue that accumulates in various malignant tumors because of their high glucose metabolic rates. The purpose of the study was to develop a PET method to detect small CC tumors in patients with PSC. PET scanning of the liver was performed after intravenous injection of 200 MBq FDG in 9 patients with PSC, 6 patients with PSC + CC, and 5 controls. The scanning was performed at successive time intervals for a total of 90 minutes with simultaneous successive arterial blood sampling for radioactivity concentration determination. In each of the PSC + CC patients, 2 to 7 "hot spots" were seen, with volumes of 1.0 to 45 mL (median, 4.4 mL). There were no hot spots in the two other patient groups. The localization of hot spots was confirmed by single-blind evaluation. Data were analyzed by the Gjedde-Patlak plot, yielding values of the net metabolic clearance of FDG, K [mL min(-1) 100 mL(-1) tissue]. In the CC hot spots, maximum K values were 1.59 to 4.17 (median, 2.34; n = 6); in the reference liver tissues of these patients, K values were 0.40 to 0.69 (median, 0.49); in PSC patients, they were 0.23 to 0.53 (median, 0.36); and in controls, they were 0.20 to 0.34 (median, 0.31). The difference between K in CC hot spots and the other groups was statistically significant (P < .001). We conclude that FDG-PET seems to be able to detect small CC tumors and may be useful in the therapeutic management of PSC.     

Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis

Overlapping features between primary sclerosing cholangitis (PSC and autoimmune hepatitis (AIH) have previously been noted. To assess systematically similarities between these disorders, we have evaluated 114 PSC patients (36 women; 78 men), all confirmed by endoscopic retrograde cholangiography (ERC), according to a scoring system proposed by The International Autoimmune Hepatitis Group for the diagnosis of AIH. The scoring system attributes positive or negative scores to the parameters sex, ratio of elevation of serum levels of alkaline phosphatase (ALP) vs. aminotransferase, serum levels of immunoglobulins and autoantibodies, viral markers, history of drug and alcohol intake, genetic factors, liver histology, and response to therapy. Two of the PSC patients (2%) obtained scores above 15 before treatment, satisfying the diagnostic criterion of "definite" AIH. Thirty-eight patients (33%) scored between 10 and 15 points and could be classified as "probable" AIH. The serum level of immunoglobulin G (IgG) was elevated in 68 patients (61% of 111 cases tested), and positive titers of antinuclear antibodies (ANA) or smooth muscle antibodies (SMA) were detected in 24 patients (22% of 111 cases tested). Thirty-five of the PSC patients (33% of 105 evaluable biopsy specimens) obtained positive scores for histological features similar to those of AIH, but the total score for histology was in the negative range in 72 patients (69%) because of the presence of biliary changes. The frequent finding of high scores in PSC patients underlines the similarities PSC may have with AIH. A modification of the scoring system, in particular by increasing the negative score for histological biliary changes, would improve its potential to discriminate between AIH and PSC.     

Bile duct bacterial isolates in primary sclerosing cholangitis: a study of explanted livers

BACKGROUND/AIMS: The pathogenesis of the inflammatory lesion in primary sclerosing cholangitis is unknown. The clinical picture is characterized by i.a. episodes of fever, the cause of which also remains speculative. Previous studies of bacterial isolates in the liver or bile ducts in primary sclerosing cholangitis have had the shortcoming of possible contamination associated with the sampling. The aim of this study was to investigate whether bile and bile duct tissue, obtained under sterile conditions in connection with liver transplantation, contain bacteria. METHODS: We studied bile from bile duct walls and bile collected from the explanted livers of 36 patients with primary sclerosing cholangitis and 14 patients with primary biliary cirrhosis. RESULTS: Positive cultures were obtained from 21 of 36 primary sclerosing cholangitis patients, but from none of the primary biliary cirrhosis patients. The number of bacterial strains was inversely related to the time after the last endoscopic retrograde cholangiography. Treatment with antibiotics or intraductal stent, or the occurrence of fever before liver transplantation did not seem to influence the culture results, whereas antibiotic treatment in connection with endoscopic retrograde cholangiography may possibly have reduced the number of isolates in the cultures. Alpha-haemolytic Streptococci were retrieved as late as 4 years after the last endoscopic retrograde cholangiography. Retrospective analysis of liver laboratory tests after endoscopic retrograde cholangiography did not indicate a deleterious effect of the investigation. CONCLUSIONS: The data suggest that antibiotics should be given routinely in connection with endoscopic retrograde cholangiography. They also raise the question of a possible role of alpha-haemolytic Streptococci in the progression of primary sclerosing cholangitis.     

Anti-lactoferrin antibodies and other types of ANCA in ulcerative colitis, primary sclerosing cholangitis, and Crohn''s disease

A novel active-site directed specific inhibitor of phospholipase A2 (PLA2), 1-hexadecyl-3-trifluoroethylglycero-sn-2-phosphomethanol (MJ33), administered endotracheally co-dispersed in liposomes, significantly reduced the formation of thiobarbituric acid reactive substances (TBARS) in isolated rat lungs subjected to ischemia-reperfusion. Elevated conjugated dienes were unaffected. This contrasts with the effects of the cyclo-/lipoxygenase inhibitor 5,8,11,14-eicosatetraynoic acid (ETYA), which decreased formation of both TBARS and conjugated dienes (CD). The effects of MJ33 plus ETYA were additive for TBARS but results for CD were similar to ETYA alone. A similar dissociation of inhibition of TBARS and CD formation by MJ33 was observed with t-butyl hydroperoxide induced lipid peroxidation of isolated lung microsomes. Assay of lung homogenate with phosphatidylcholine as substrate showed that MJ33 selectively inhibited the Ca(2+)-independent acidic PLA2. MJ33 had no effect on thromboxane B2 release by the isolated lung, indicating the effects of acidic PLA2 inhibition do not involve the arachidonate cascade. MJ33 also partially prevented lung edema and lactate dehydrogenase release associated with ischemia-reperfusion. The observations show that this PLA2 inhibitor can be delivered to oxidant-sensitive lung sites by its co-dispersal in liposomes, and that oxidant-induced lipid peroxidation in this model of lung injury occurs in a complex lipid prior to PLA2 activity.     

Perinuclear antineutrophil cytoplasmic antibodies in patients with Crohn's disease define a clinical subgroup

BACKGROUND & AIMS: Antineutrophil cytoplasmic antibodies (ANCA) have been consistently detected in a subgroup of patients with Crohn's disease (CD). This study was designed to determine whether serum ANCA expression in patients with CD characterizes an identifiable clinical subgroup. METHODS: The study population consisted of 69 consecutive patients with an established diagnosis of CD as determined by a combination of characteristic clinical, radiographic, endoscopic, and histopathologic criteria. Sera from the patients were analyzed for the presence of ANCAs using the fixed neutrophil enzyme-linked immunosorbent assay (ELISA) assay. Perinuclear ANCA (pANCA)-positive and cytoplasmic ANCA (cANCA)-positive results by ELISA were confirmed by indirect immunofluorescence staining. Clinical profiles of the ANCA-positive patients with CD were compared with those of patients with CD not expressing ANCA (ANCA-negative). RESULTS: pANCA-positive patients with CD have endoscopically and/or histopathologically documented left-sided colitis and symptoms of left-sided colonic inflammation, clinically reflected by rectal bleeding and mucus discharge, urgency, and treatment with topical agents. One hundred percent of patients with CD expressing pANCA had "UC-like" features. CONCLUSIONS: In patients with CD, serum pANCA expression characterizes a UC-like clinical phenotype. Stratification of CD by serum pANCA provides evidence of heterogeneity within CD and suggests a common intestinal mucosal inflammatory process among a definable subgroup of patients with CD and UC expressing this marker.     

Endoscopic management of biliary tract strictures in primary sclerosing cholangitis

BACKGROUND AND STUDY AIMS: In a subgroup of patients, primary sclerosing cholangitis (PSC) is complicated by high-grade focal strictures of the bile ducts, and this can have an unfavorable influence on the natural course of the disease. The aim of this study was to evaluate the efficacy and safety of endoscopic treatment in this selected patient group. PATIENTS AND METHODS: Twelve symptomatic patients with primary sclerosing cholangitis and major ductal strictures were included in a prospective study of endoscopic treatment. All patients were managed by repeated angioplasty-type balloon dilation and nasobiliary catheter perfusion. A minimum of two treatment sessions was used, and therapy was continued until satisfactory reopening of the strictures was obtained. Routine endoscopic follow-up was performed after three, six, 12, 18, and 24 months, and then at yearly intervals. The efficacy of therapy was assessed by evaluating clinical symptoms, laboratory data, and cholangiograms. RESULTS: The long-term follow-up averaged 23 months (range: 12-50 months). Two to nine (mean: three) treatment sessions were required to obtain satisfactory reopening of major biliary strictures. Eight patients showed considerable and sustained improvement. The mean serum bilirubin, alkaline phosphatase, gamma-glutamyl-transpeptidase, and alanine aminotransferase levels felt significantly by 73% (P = 0.0164), 46% (P = 0.0022), 55% (P = 0.0022), and 58% (P = 0.0022), respectively. The average radiographic stricture score before treatment was 3.2 +/- 0.8 (P = 0.0033). Three patients required liver transplantation seven, 12, and 40 months after the initiation of endoscopic treatment, due to a deterioration in hepatic function or an inability to exclude complex biliary malignancy. No major procedure-related side effects were observed. CONCLUSIONS: Our results suggest that the endoscopic treatment of PSC patients with dominant bile duct strictures is effective, safe, and well-tolerated. However, it is important not to overlook the potential development of cholangiocarcinoma.     

Rare initial manifestation and differential diagnosis of primary sclerosing cholangitis

BACKGROUND: Primary sclerosing cholangitis is most often diagnosed in middle-aged men who are suffering from inflammatory bowel diseases. CASE REPORT: A young, previously healthy woman presents with icterus of acute onset, high transaminases and positive hepatitis B virus serology. Ultrasound and nuclear magnetic resonance images demonstrate multiple liver tumors. After acute viral hepatitis as well as primary or secondary malignant liver tumors have been excluded as underlying diseases, diagnosis of primary sclerosing cholangitis is made. CONCLUSION: Differential diagnosis of primary sclerosing cholangitis should also be considered in cases with untypical primary presentation.     

Factors related to the presence of IgA class antineutrophil cytoplasmic antibodies in ulcerative colitis

OBJECTIVES: Few studies have assessed the IgA antineutrophil cytoplasmic antibody (ANCA) positivity in ulcerative colitis patients and there is no information about factors related to its synthesis and its status after colectomy. The aims of the study were to assess the serum IgA ANCA prevalence in ulcerative colitis patients, both nonoperated and operated, and to determine the clinical factors related to this positivity. METHODS: Fifty-four ulcerative colitis patients, 63 ulcerative colitis colectomized patients (32 with Brooke's ileostomy and 31 with ileal pouch anal anastomosis), and 24 controls were studied. Antineutrophil cytoplasmic antibodies were detected by specific indirect immunofluorescent assays. RESULTS: The percentage of IgA ANCA was significantly higher in patients with ileal pouch anal anastomosis (45%) than in patients with Brooke's ileostomy (22%). There were no differences related to the presence of pouchitis in ileal pouch anal anastomosis patients. Patients with nonoperated extensive colitis (47%) had a significantly higher percentage of IgA ANCA than patients with proctitis (19%). Total percentage of ANCA (IgA and/or IgG) tended to be higher in ulcerative colitis and in patients with ileal pouch anal anastomosis than in patients with Brooke's ileostomy. However, in ileal pouch anal anastomosis patients, ANCA positivity was mainly due to exclusive IgA production. CONCLUSIONS: A substantial percentage of ulcerative colitis patients, and especially colectomized patients with ileal pouch anal anastomosis, had IgA ANCA, suggesting that ANCA production in ulcerative colitis might be stimulated by an immune reaction in the intestinal mucosa.     

Hepatic hilar inflammatory pseudotumor mimicking cholangiocarcinoma with cholangitis and phlebitis--a variant of primary sclerosing cholangitis?

Inflammatory pseudotumor (IPT) of the liver is rare. We present a case of hepatic IPT mimicking cholangiocarcinoma in which the tumor was located at the left porta hepatis. The patient was a 64-year-old man in whom abnormal liver function test results had been noted incidentally during an annual health checkup in 1993: the patient declined to go to the hospital for further examination. At the annual health checkup the following year, abnormal liver function test results were noticed again, and this time he did go to a hospital, where a hepatic mass was found. Laboratory test results were unremarkable. Based on the location of the lesion and the findings of a variety of imaging modalities, such as ultrasound and computed tomography examination, the lesion was preoperatively diagnosed as hilar cholangiocarcinoma and was surgically resected. Pathologic examination of the resected lesion, however, revealed that it was not a true tumor but an inflammatory pseudotumor with marked destructive and sclerosing cholangitis mimicking primary sclerosing cholangitis (PSC) and obliterative phlebitis. Since the location and features of the tumor in the present case are very pertinent to the relationship between IPT and PSC, we describe its clinical and histologic features and discuss the findings in relation to PSC in the context of our literature review.     

Abnormal accumulation of endotoxin in biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis

We measured levels of glucose and glycated hemoglobin in the blood of three of the world's smallest nectarivorous birds, the Anna's (Calypte anna), Costa's (Calypte costae), and ruby-throated hummingbirds (Archilochus colubris). Plasma glucose levels of hummingbirds that were fasted overnight (17 mM) were higher than those in any mammal and are among the highest ever measured in a fasting vertebrate. Glucose levels in hummingbirds just after feeding were extreme, rising as high as 42 mM. The surprisingly high blood glucose concentrations in hummingbirds were accompanied by glycated hemoglobin levels that are the highest ever measured in birds but are lower than those of non-diabetic humans. How hummingbirds tolerate blood glucose levels that cause serious neurological and microvascular pathologies in diabetic humans and animals remains unknown.     

Liver transplantation in a 29-year-old patient with gallbladder carcinoma complicating primary sclerosing cholangitis

Patients with primary sclerosing cholangitis (PSC) are at increased risk for cholangiocarcinoma. This tumor usually is a fatal complication, median survival after diagnosis is less than six months. In an asymptomatic 29-year-old patient with long-standing PSC and ulcerative colitis, routine abdominal ultrasound demonstrated an irregular mass, 11 x 13 mm, in the gallbladder. Cholecystectomy was performed, and histological examination demonstrated a moderately differentiated adenocarcinoma with infiltration of all layers of the gallbladder and invasion of local lymphatic vessels. Extensive diagnostic work-up failed to consistently demonstrate metastatic disease, and the patient was offered a liver transplantation. 24 months after the operation, the patient feels well and there is no indication of tumor recurrence. In carefully selected patients with gallbladder carcinoma complicating PSC, liver transplantation may be a therapeutic option.     

Bone disease in patients with primary sclerosing cholangitis: prevalence, severity and prediction of progression

BACKGROUND/AIMS: Osteopenia is a common complication in some chronic cholestatic liver diseases. Our aims were to determine the prevalence and severity of bone disease in patients with primary sclerosing cholangitis; and identify risk factors to predict the presence and progression of osteopenia. METHODS: Eighty-one patients involved in a randomized trial of ursodeoxycholic acid were analyzed. Bone mineral density of the lumbar spine was determined at entry and at annual intervals. RESULTS: Bone mineral density of the lumber spine in primary sclerosing cholangitis patients was significantly lower than expected when compared to normal values adjusted for age, sex and ethnic group at entry (p<0.005), and after 1 year (p<0.05), 2 years (p<0.05), 4 years (p<0.005) and 5 years of follow-up (p<0.005). Seven patients (8.6%) had bone mineral density of the lumber spine below the fracture threshold at entry. These patients were significantly older, had a longer duration of inflammatory bowel disease and more advanced primary sclerosing cholangitis. The rate of bone loss in primary sclerosing cholangitis patients and expected in normal controls was 0.01+/-0.02 g x cm(-2) x year(-1) and 0.003+/-0.003 g x cm(-2) x year(-1), respectively (p = NS), and was similar in patients receiving placebo and ursodeoxycholic acid. Age was the only variable inversely related with baseline bone mineral density of the lumber spine (p<0.0001). None of the variables predicted progression of the bone disease. CONCLUSIONS: Severe osteoporosis occurs in few patients with primary sclerosing cholangitis, but it should be suspected in patients with longer duration of inflammatory bowel disease and more advanced liver disease. Its presence, severity and progression cannot be accurately evaluated by routine clinical, biochemical, or histological variables. Ursodeoxycholic acid does not affect the rate of bone loss in primary sclerosing cholangitis.     

Three paediatric cases of primary sclerosing cholangitis treated with ursodeoxycholic acid and sulphasalazine

The aim of this study was to reveal the relationship of the plasma levels of the carboxy terminal propeptide of type I procollagen (PICP) and the pyridinoline cross-linked carboxyterminal telopeptide domains of type I collagen (ICTP) to age and height velocity (HV), and to compare PICP and ICTP levels in those who have not reached their final height with those who have. PICP and ICTP levels were measured by RIA in 271 healthy children (161M, 110F) aged from 10 to 15 y. The HV was calculated from their health check-up cards. The subjects were divided into two groups in this study: the final height (FH) group whose HV was <1.0 cm/y, and the non-final height (NFH) group whose HV in the last year was > or =1.0 cm/y. PICP and ICTP levels almost paralleled the values of age-related changes of HV. Furthermore PICP and ICTP levels significantly correlated with HV. PICP and ICTP levels of the FH group were higher than those of adults previously reported. The values will be useful as reference for healthy children and growth disorder. Before reaching final height, PICP and ICTP can be useful makers of not only bone turnover but also of linear growth. Bone turnover rate is still increasingly active just after linear growth has been completed, and then it become similar to the levels of adults.     

Biliary lactoferrin concentrations are increased in active inflammatory bowel disease: a factor in the pathogenesis of primary sclerosing cholangitis?

We have used the whole-cell patch-clamp technique to study the effects of inositol 1,4,5,6-tetrakisphosphate [Ins(1,4,5,6)P4], inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P4] and inositol 1,3, 4,5,6-pentacisphosphate [Ins(1,3,4,5,6)P5] on volume-activated Cl- currents (ICl,vol) in cultured endothelial cells from bovine pulmonary artery (CPAE cells). Ins(1,4,5,6)P4 and Ins(3,4,5,6)P4 were applied intracellularly via the patch pipette at concentrations between 10 and 100 muM. Both tetrakisphosphates inhibited the Cl- current ICl,Ca, which was activated by intracellular loading of the cells with 500 nM Ca2+ [for inhibition by Ins(1,4,5,6)P4: 58% at 10 muM, 75% at 100 muM; for Ins(3,4,5,6)P4: 44% at 10 muM, 65% at 100 muM]. Inhibition of ICl,Ca occurred without significant changes in its kinetic properties. The amplitude of ICl,vol activated by a 13.5 or 27% hypotonic solution at +100 mV was strongly reduced in cells loaded with either tetrakisphosphate, i.e. a 73% reduction for Ins(3,4,5,6)P4 and 89% for Ins(1,4,5,6)P4 at 100 muM. Both tetrakisphosphates also inhibited a current probably identical to ICl,vol which was activated by dialysing the cell with 100 muM guanosine 5'-O-(3-thiotriphosphate) (GTP[gamma-S]). Ins(1, 3,4,5,6)P5 at a concentration of 30 muM did not significantly reduce ICl, vol. The effects of Ins(3,4,5,6)P4 may represent an inhibitory pathway for the ICl,Ca and ICl,vol in macrovascular endothelium after sustained receptor-mediated activation of phospholipase C.     

Ursodeoxycholic acid does not improve the clinical course of primary sclerosing cholangitis over a 2-year period

BACKGROUND: Ursodeoxycholic acid has been shown to be a useful agent in the clinical management of patients with primary biliary cirrhosis and autoimmune chronic active hepatitis. Its efficacy is presumed to be based upon its ability to act as a detergent and to incite a choleresis. Recent additional data suggest it also reduces HLA antigen expression on liver and biliary epithelial cells and impairs T cell reactivity. METHODS: A randomized controlled study of 59 patients with primary sclerosing cholangitis was performed over a 24 months period with 3 groups being studied. Group I consisted of 20 patients who were given ursodeoxycholic acid 300 mg orally twice a day; group II consisted of 19 patients who were given colchicine 0.6 mg orally BID; and group III was an untreated medical control group. All three groups were seen at regular 3-month intervals and had quarterly, annual and terminal studies performed to assess their disease status. RESULTS: No difference between groups was evident after two full years of therapy when parameters of liver injury, liver function, liver size and hepatic copper content were compared between groups. Similarly, no difference in ERCP findings was evident between groups either at entry or after two years of therapy. CONCLUSIONS: These data suggest that ursodeoxycholic acid is no better than colchicine or simple medical follow-up. Thus, neither ursodeoxycholic acid or colchicine can be considered to be effective therapies for primary sclerosing cholangitis.     

Survival and risk of cholangiocarcinoma in patients with primary sclerosing cholangitis. A population-based study

BACKGROUND: Endoscopic retrograde cholangiopancreatography was introduced in the early 1970s, making a more reliable diagnosis of primary sclerosing cholangitis (PSC) possible. Since then decreased survival and increased risk of cholangiocarcinoma have been reported. However, no population-based studies have quantified these outcomes. METHODS: A population-based cohort of 125 patients with a verified PSC diagnosis was followed up through linkage to the Swedish Death Registry and the Swedish Cancer Registry for occurrence of death and cholangiocarcinoma. RESULTS: The diagnosis of PSC was associated with a substantially decreased survival, with an overall 10-year survival of 68.8%. Patients with a diagnosis of inflammatory bowel disease (IBD) had a somewhat better prognosis, 71.8%, compared with 60% for patients without. Fourteen subsequent cholangiocarcinomas yielded a cumulative risk of 11.2% 10 years after diagnosis. Sex, duration of IBD, and colectomy influenced neither the survival nor the cholangiocarcinoma risk. CONCLUSION: Patients with PSC have a substantially decreased survival, which is most pronounced among patients without IBD.     

A possible defective estimation of antineutrophil cytoplasmic antibodies in systemic lupus erythematosus due to the coexistence of periodontitis: preliminary observations

The Family Environment Scale has been used extensively in family research since first being published. However, despite its appeal both conceptually and empirically, doubts have been raised over the scale's reliability. This article presents normative and reliability data for the Family Environment Scale from a large, combined sample of adolescents. Means and standard deviations were generally found to be in line with those reported in the scale's manual; however, estimates of internal consistency for most subscales could be considered inadequate for research purposes.